3,4-Dihydroquinazoline derivatives as T-type calcium channel blockers and method of preparing the same

The present invention relates to 3,4-dihydroquinazoline derivatives as T-type calcium channel blockers and a method of preparing the same. The present invention further relates to a composition comprising the same. The composition comprising the 3,4-dihydroquinazoline derivatives of the present invention can be effectively used for preventing and treating angina pectoris, high blood pressure, myocardial disease, pain and epilepsy by blocking the T-type calcium channel.

Skip to: Description  ·  Claims  · Patent History  ·  Patent History
Description
FIELD OF THE INVENTION

The present invention relates to 3,4-dihydroquinazoline derivatives or a salt thereof as T-type calcium channel blockers and a method of preparing the same. The present invention further relates to a composition comprising the same for blocking the T-type calcium channel.

BACKGROUND OF THE INVENTION

Calcium in nerve cells plays an important role in transferring signals between the nerve cells. There are several channels for calcium. However, when a terminal stimulus is transferred thereto, a voltage-dependent Ca2+ channel works primarily. That is, the voltage-dependent Ca2+ channel as a membrane protein regulates various intracellular functions (e.g., muscle contraction, neurogenesis, synapse plasticity, secretion of neurotransmitter and hormone, gene expression, etc.) by controlling an inflow of calcium ion from a cell exterior.

The voltage-dependent Ca2+ channel can be functionally classified into two groups depending on its biophysical property: a low voltage-activated Ca2+ channel (hereinafter referred to as “LVA”), which is activated at lower voltage; and a high voltage-activated Ca2+ channel (hereinafter referred to as “HVA”), which is activated at higher voltage. The HVA calcium channel is subdivided into L-, P/Q-, N- and R-types depending on a pharmacological property of the current induced thereby The LVA calcium channel is characterized by small conductivity being very quickly activated and inactivated. Thus, it belongs to T (transient)-type calcium channel (Tsien, R. W. et al., Trends Neurosci. 1988, 11, 431-438).

It has been reported that the T-type calcium channel is involved in bursting firing of nerve cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), pacemaker activity of the heart (Zhou, Z. et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of aldosterone (Rossier, M. F. et al., Endocrinology 1996, 137, 4817-4826), fertilization (Arnoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009) and pain relief (Ikeda, H. et al., Science 2003, 299, 1237-1240).

The T-type calcium channel may become over-expressed due to genetic or environmental causes, such as epilepsy (Tsakiridou, E. et al., J. Neurosci. 1995, 15, 3110-3117), high blood pressure (Self, D. A. et al., J. Vacs. Res. 1994, 31, 359-366), ventricular hypertrophy (Nuss, H. B. et al., Circ. Res. 1995, 73, 777-7825), pain (Shin, H. S. et al., Science 2003, 302, 117-119), and angina pectoris (Van der Vring, J. A. et al., Am. J. Ther. 1999, 6, 229-233). It has been found that there are three types of genes, α1G, α1H and α1I, in the T-type calcium channel through gene cloning techniques (Talley, E. M. et al., J. Neurosci. 1999, 19, 1895-1911). There have been numerous attempts to develop a blocking agent, which selectively inhibits the T-type calcium channel. However, there were no effective T-type calcium channel blockers except for Mibefradil and ZD7288 (Felix, R. et al., Biochem. Biophys. Res. Commun. 2003, 311, 187-192). Accordingly, by developing a selective T-type calcium channel blocker, it may be possible to develop an epochal treating agent for epilepsy, high blood pressure and pain-related diseases.

A representative drug for blocking the T-type calcium channel is Mibefradil of Hoffman La Roche Ltd. (registered trademark: Posicor). The drug was found to be effective in treating high blood pressure, angina pectoris and cerebral apoplexy. It has been placed in the market as a treating agent for high blood pressure since May of 1997. However, a side effect caused by a drug-drug interaction due to inhibition of CYP 3A4 hepatic enzyme was discovered. As such, the drug was withdrawn from the market on June of 1999, which was just 13 months from first entering the market.

Accordingly, there has been a need in the art to develop a selective T-type calcium channel blocker, which has a new structure that can substitute Mibefradil.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a T-type calcium channel blocker having a new structural backbone, which shows therapeutic effects superior to Mibefradil without causing any side effects.

Specifically, the present invention provides novel 3,4-dihydroquinazole derivatives of Formula 1 or a salt thereof, which can be effectively used as selective T-type calcium channel blockers, and a method of preparing the same. Further, the present invention provides a composition comprising the same and a pharmaceutically acceptable carrier for blocking the T-type calcium channel. Furthermore, the present invention provides a method of treating a disorder selected from the group consisting of angina pectoris, high blood pressure, myocardial disease, pain and epilepsy by administering a therapeutically effective amount of a 3,4-dihydroquinazoline derivative or a pharmaceutically acceptable salt thereof

    • wherein, n is an integer ranging from 1 to 4;
    • R1 is selected from the group consisting of hydrogen, hydroxy, halogen, nitro, C1-C8 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted aryl and heteroaryl, C1-C6 alkoxy, C3-C6 cycloalkoxy, (aryl or heteroaryl)oxy, C1-C6 thioalkoxy, C3-C6 cyclothioalkoxy, (aryl or heteroaryl)thiooxy and amino;
    • R2 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkoxya C1-C6 alkenyl; substituted or unsubstituted aryl and heteroaryl; 4-morpholinyl; piperazinyl having a random substituent at the 4th position; 1-pyrrolidinyl; 1-piperidinyl; or —NR1R2, wherein R1 and R2 are each independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl and heteroaryl;
    • R3 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkoxyalkyl, substituted or unsubstituted aryl and heteroaryl;
    • R4 is X—(CH2)n—Y—S(O)m—NH-Z, wherein X is oxygen or nitrogen; n is an integer ranging from 1 to 4; Y is substituted or unsubstituted C3-C6 cycloalkyl, aryl or heteroaryl; m is an integer ranging from 0 to 2; Z is selected from the group consisting of substituted or unsubstituted C3-C6 cycloalkyl, aryl and heteroaryl.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the property of T-type calcium channel, which is activated mostly at a low voltage of −30 mV.

FIG. 2 is a graph showing the property of T-type calcium channel in which the activated current is quickly activated and inactivated.

FIG. 3 is a graph showing the inhibitory effect of T-type calcium channel caused by Ni2+.

FIG. 4 is a graph showing the inhibitory effect of Mibefradil on T-type calcium channel.

FIG. 5 is a graph showing the inhibitory effect of the compound of the present invention on T-type calcium channel.

FIG. 6 is a graph showing the cytotoxicity of the compound of the present n.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present disclosure is based on investigations of 3,4-dihydroquinazole deriatives, which are effective for selectively blocking the T-type calcium channel.

Representative examples of the preferred compounds of Formula 1 of the present invention are:

    • 4-(N-benzylacetamido)-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline (KYS05001),
    • 4-(N-benzylacetamido)-3-phenyl-2-(morpholin-1-yl)-3,4-dihydroquinazoline (KYS05026),
    • 4-(N-benzylacetamido)-3-phenyl-2-(4-methylpiperazinyl)-3,4-dihydroquinazoline (KYS05028),
    • 4-[N-(4-nitrobenzyl)acetamido]-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline (KYS05034)
    • 4-{N-[4-(4-methylbenzenesulfonylamido)benzyl]acetamido}-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline (KYS05041), and
    • 4-{N-[4-(4-fluorobenzenesulfonylamido)benzyl]acetamido}-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline (KYS05042). The respective formulas of the compounds described above are as follows:

The compound of the present invention may be prepared by such processes as shown in the Reaction Schemes 1 and 2, which are given for the purposes of illustration only and are not intended to limit the scope of the present invention.

A carbodiimide compound (4) as an intermediate of the compound of the present invention can be synthesized according to a conventional method described by Wang, F., et al. (Tetrahedron Lett. 1997, 38, 8651-8654) if properly modified. In a preferred embodiment of the present invention, methyl 2-nitrocinnamate (1) as a starting material is treated with SnCl2 at an appropriate temperature (preferably 70 ° C.) to reduce a nitro group into an amine group. Generally, the carbodiimide is prepared through aza-Wittig reaction between iminophosphoranes and hetero-cumulenes (isocyanate or tioisocyanate) (Wamhoff, H. et al., Adv. Heterocycl. Chem. 1995, 64, 159; Molina, P. et al., Synthesis 1994, 1197-1217). However, the preparation of a urea-type compound, rather than that of the iminophosphorane having three phenyl rings, gives quantitative yield rate at a room temperature. Thus, its reaction condition is simpler. As such, the present invention employs a method of synthesizing the carbodiimide from a urea-type compound.

Accordingly, an amine compound (2) thus obtained is dissolved in tetrahydrofuran (THF) or benzene (preferably benzene), in which phenylisocinate is added thereto. Then, the mixture is stirred at a room temperature in order to obtain a urea-type compound (3). The urea-type compound is subjected to dehydration reaction using dibromotriphenylphosphine and triethylamine to obtain the carbodiimide compound (4) (Gololobov, Y G. et al., Tetrahedron 1992, 48, 1353-1406; Larksarp, C. et al., J. Org. Chem. 1998, 63, 6229-6233). In this step, if phenylisocyanate is replaced by isocyanate or tioisocyanate, it is capable of incorporating various substituents at the third position of dihydroquinazoline.

When the carbodiimide compound (4) reacts with various heteroatomic nucleophils such as alcohol, thioalcohol and amine (preferably piperidine in Reaction Scheme 1) under the presence of a solvent (e.g., benzene), the heteroatom carries out nucleophil adding reaction to a central carbon of the carbodiimide group. The compound (5) is subjected to intermolecular sequential 1,4-addition reaction in order to obtain 3,4-dihydroquinazoline (6) as an intermediate of the compound of the present invention.

A methyl ester group of the intermediate compound (6) of the present invention is hydrolyzed into lithium hydroxide in a solvent mixture of THF and water at a proper temperature (preferably 60° C.) to obtain a free carboxylic compound (7) quantitatively. The free carboxylic compound (7) is subjected to a coupling reaction with various alcohol and amine (preferably nitrobenzylamine in Reaction Scheme 2) by using 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloric acid (EDC) and 1-hydroxybenzotriazole (HOBT) in order to obtain an amido compound (8) (Gaucher, A. et al., Tetrahedron: Asymmetry 2001, 12, 2571-2580; Dhaon, M. K. et al., J. Org. Chem. 1982, 47, 1962-1965). The amido compound (8) is subjected to hydrogenation to reduce its nitro group into an amino group under the presence of methanol as a solvent and palladium (Pd) as a catalyst. This is to obtain an amine compound (9). The amine compound (9) is subjected to a coupling reaction with various sulfonylhalide (preferably 4-fluorobenzenesulfonyl chloride in Reaction Scheme 2) to obtain a sulfonamido compound (10), which is the final compound of the present invention.

The present invention will now be described in detail with reference to the following examples, which are not intended to limit the scope of the present invention.

EXAMPLE 1 Preparation of methyl 2-aminocinnamate (2)

Methyl 2-nitrocinnamate (1) (0.202 g, 0.975 mmol) was dissolved in 20 ml of ethyl acetate and SnCl2.2H2O (1.11 g, 4.87 mmol) was added thereto. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was cooled to a room temperature. The reaction mixture was adjusted to a weak alkaline solution with a saturated sodium bicarbonate solution and then filtered with fine clay layer (Celite 545). A water layer was extracted with ethyl acetate three times, in which an organic layer collected therefrom was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (hexane:ethyl acetate=5:1) to purify the title compound (2) in the form of a yellow crystal (0.161 g, 93%) (mp 67° C.).

IR (KBr) 3365, 2364, 1704, 1622, 1330, 1198, 756 cm−1; 1H NMR (300 MHz, CDCl3) 67 7.86 (d, J=15.9 Hz, 1H, —CH═CH—O2Me), 7.40 (d, J=7.5 Hz, 1H, aromatic), 7.19 (t, J=7.2 Hz, 1H, aromatic), 6.78 (t, J=7.8 Hz, 1H, aromatic), 6.72 (d, J=7.5 Hz, 1H, aromatic), 6.38 (d, J=15.9 Hz, 1H, —CH═CH—CO2Me) 4.02 (br, 2H, —NH2), 3.82 (s, 3H, —OCH3); 13C NMR (75 MHz, CDCl3) δ 168.0, 145.9, 140.6, 131.6, 128.3, 120.1, 119.2, 117.9, 117.0, 51.9.

EXAMPLE 2 Preparation of methyl 3-[2-(3-phenylureido)phenyl]acrylate (3)

Methyl 2-aminocinnamate (2) (6.35 g, 35.8 mmol) was dissolved in 150 ml of benzene and phenylisocyanate (5.12 g, 43.0 mmol) was slowly dropped thereto at a room temperature. The reaction mixture was stirred for 12 hours to obtain a solid precipitate. Then, the precipitate was washed with ether in order to obtain the title compound (3) in the form of a white crystal (10.2 g, 96%) (mp 184° C.).

IR (KBr) 3346, 3278, 1724, 1650, 1548, 1322, 1172, 758, 672 cm1; 1H NMR (300 MHz, DMSO) δ 8.94 (s, 1H, —NH—CO—) 8.49 (s, 1H, —NH—CO—) 7.89 (d, J=15.9 Hz, 1H, —CH═CH—CO2Me), 7.76 (d, J=7.8 Hz, 2H, aromatic), 7.46 (d, J=8.4 Hz, 2H, aromatic) 7.39 (t, J=8.1 Hz, 1H, aromatic), 7.28 (t, J=7.8 Hz, 2H, aromatic) 7.12 (t, J=7.5 Hz, 1H, aromatic) 6.97 (t, J=7.8 Hz, 1H, aromatic), 6.58 (d, J=15.3 Hz, 1H, —CH═CH—CO2Me), 3.73 (s, 3H, —OCH3); 13C NMR (75 MHz, DMSO) δ 167.4, 153.5, 140.5, 140.3, 138.5, 131.4, 129.5, 127.8, 126.8, 124.6, 124.4, 122.7, 119.5, 118.9, 52.2.

EXAMPLE 3 Preparation of methyl 3-[2-(phenyliminomethyleneamino)phenyl]acrylate (4)

The compound (3) (6.04 g, 20.4 mmol) and triethylamine (6.19 g, 61.2 mmol) were dissolved in 30 ml of dichloromethane and dibromotriphenyl-phosphine (12.9 g, 30.6 mmol) was gently added thereto at 0 ° C. The reaction mixture was stirred for 1 hour and extracted with dichloromethane three times. An organic layer collected therefrom was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (hexane:ethyl acetate=20:1) to purify the title compound (4) in the form of a white crystal, carbodjimide (4), (4.26 g, 75%) (mp 54° C.).

IR (KBr) 2142, 1716, 1484, 1172, 756, 59 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=16.2 Hz, 1H, —CH═CH—CO2Me), 7.56 (d, J=7.8 Hz, 1H, aromatic), 7.36-7.29 (m, 3H, aromatic), 7.25 (d, J=7.8 Hz, 1H, aromatic), 7.20-7.13 (m, 4H, aromatic), 6.52 (d, J=16.2 Hz, 1H, —CH═CH—CO2Me), 3.80 (s, 3H, —OCH3); 13C NMR (75 MHz, CDCl3) δ 167.5, 140.5, 138.4, 138.0, 134.3, 131.3, 129.8, 129.0, 127.8, 126.1, 126.0, 125.9, 124.6, 119.6, 52.0.

EXAMPLE 4 Preparation of 4-methoxycarbonylmethyl-2-(1-piperidinyl)-3-phenyl-3,4-dihydroquinazoline (6)

The compound (4) (0.605 g, 2.17 mmol) was dissolved in 20 ml of benzene and piperidine (0.222 g, 2.60 mmol) was gently dropped thereto at a room temperature. The reaction mixture was stirred for 2 hours. After 2 hours, the reaction mixture was washed with water and brine. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (CH2Cl2:MeOH=10:1) to purify the title compound (6) in the form of a white crystal (0.632 g, 80%) (mp 109° C.).

1H NMR (300 MHz, CDCl3) δ 7.28-7.17 (m, 4H, aromatic), 7.09-7.01 (m, 3H, aromatic), 6.97-6.89 (m, 2H, aromatic), 5.10 (dd, J=4.5 and 10.8 Hz, 1H, —CH2—CH—N—), 3.79 (s, 3H, —OCH3), 3.42 (s, 4H, piperidinyl), 2.85 (dd, J=10.8 and 15.3 Hz, 1H, —CO—CH2—), 2.52 (dd, J=4.7 and 15.5 Hz, 1H, —CO—CH2—), 1.55-1.50 (m, 2H, piperidinyl), 1.43-1.40 (m, 4H, piperidinyl); 13C NMR (75 MHz, CDCl3) δ 172.2, 153.2, 146.3, 144.4, 129.4, 128.6, 126.1, 124.9, 124.1, 123.1, 122.6, 122.4, 61.2, 52.0, 47.0, 39.8, 25.7, 25.0; HRMS (FAB, M+H) Calcd for C22H26N3O2 364.2025, found 364.2019.

EXAMPLE 5 Preparation of 4-carboxy-2-(1-piperidinyl)-3-phenyl-3,4-dihydroquinazoline (7)

The compound (6) (0.235g, 0.645 mmol) was dissolved in 10 ml of THF/water (1:1) and a hydrate of lithium hydroxide (0.135 g, 3.23 mmol) was added thereto at a room temperature. The reaction mixture was stirred at 60° C. for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 3˜4 and the reaction mixture was extracted with dichloromethane three times. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure to quantitatively obtain the title compound in the form of a white crystal (7) (mp 238° C.).

1H NMR (300 MHz, DMSO) δ 7.57 (d, J=7.8 Hz, 1H, aromatic), 7.45-7.26 (m, 7H, aromatic), 7.19 (m, 1H, aromatic), 5.29 (dd, J=6.3 and 9.3 Hz, 1H, —CH2—CH—N—), 3.36 (s, 4H, piperidinyl), 2.88 (dd, J=9.3 and 15.0 Hz, 1H, —CO—CH2—), 2.69 (dd, J=6.3 and 15.1 Hz, 1H, —CO—CH2—), 1.46-1.23 (m, 6H, piperidinyl); 13C NMR (75 MHz, CD3OD) δ 174.6, 153.1, 143.7, 132.7, 130.1, 129.1, 127.5, 127.3, 126.3, 125.7, 124.7, 118.0, 62.8, 49.5, 42.6, 24.6, 23.3.

EXAMPLE 6 Preparation of 4-[N-(4-nitrobenzyl)acetamido]-2-(1-piperidinyl)-3-phenyl-3,4-dihydroquinazoline (8)

The compound (7) (0.22 g, 0.63 mmol) and 1-hydroxybenzotriazol (HOBT) (0.13 g, 0.94 mmol) were dissolved in 20 ml of dichloromethane/THF (1:1) and 4-nitrobenzylamine (0.18 mg, 0.94 mmol) was dropped thereto at 0° C. The reaction mixture was stirred at the same temperature for 1 hour. Then, 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloric acid (EDC) (0.14 g, 0.75 mmol) was added to the reaction mixture and further stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure and the resulting solution was dissolved in dichloromethane. The reaction mixture was sequentially extracted with 0.5 M hydrochloric acid aqueous solution twice. Then, it was saturated with NaHCO3 aqueous solution twice and water once and thereafter washed with brine. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (CH2Cl2:MeOH=10:1) to purify the title compound in the form of a white crystal (8) (0.24 g, 80%).

IR (KBr) 3192, 2932, 2848, 1668, 1552, 1486, 1430, 1344, 1282, 756 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.58 (br, 1H, —CO—NH—CH2—), 8.15 (d, J=8.7 Hz, 2H, —CH2—C4H4—NO2), 7.49 (d, J=8.1 Hz, 2H, —CH2—C4H4—NO2), 7.27-7.20 (m, 2H, aromatic), 7.15-7.02 (m, 4H, aromatic), 6.95-6.87 (m, 3H, aromatic), 5.23 (dd, J=6.0 and 8.7 Hz, 1H, —CH2—CH—N—), 4.67 (dd, J=6.7 and 12.1 Hz, 1H, —NH—CH2—), 4.58 (dd, J=5.7 Hz and 15.3 Hz, 1H, —NH—CH2—), 3.10 (br, 4H, piperidinyl), 2.58 (dd, J=9.0 and 14.7 Hz, 1H, —CO—CH2), 2.32 (dd, J=6.1 and 14.2 Hz, 1H, —CO—CH2—), 1.35 (br, 2H, piperidinyl), 1.13 (br, 4H, piperidinyl); 13C NMR (75 MHz, CDCl3) δ 170.9, 154.3, 147.4, 146.5, 145.9, 143.1, 129.5, 129.0, 128.5, 127.0, 125.4, 124.7, 124.0, 123.1, 123.0, 122.0, 60.8, 47.5, 43.2, 41.6, 25.2, 24.6; HRMS (FAB, M+H) Calcd for C28H30N5O3 484.2349, found 484.2341.

EXAMPLE 7 Preparation of 4-[N-(4-aminobenzyl)acetamido]-2-(1-piperidinyl)-3-phenyl-3,4-dihydroquinazoline (9)

The compound (8) (1.39 g, 2.87 mmol) and 10% Pd(C) (0.28 g) were dissolved in 40 ml of methanol and stirred for 2 hours under hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered with Celite 545 and the solvent was removed therefrom under reduced pressure. The reaction mixture was subjected to column chromatography (CH2Cl2:MeOH=10:1) to purify an amine compound (1.26 g, 97%).

IR (KBr) 3218, 2930, 2850, 1648, 1550, 1480, 1430, 1350, 1282, 732 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26-7.22 (m, 2H, aromatic), 7.20-7.11 (m, 4H, aromatic), 7.07-7.02 (m, 3H, aromatic), 6.96-6.90 (m, 2H, aromatic), 6.60-6.56 (m, 2H, aromatic), 6.37 (br, 1H, —CO—NH—CH2—), 5.17 (dd, J=5.1 and 9.6 Hz, 1H, —CH2—CH—N—), 4.32 (d, J=5.7 Hz, 2H, —NH—CH2—), 3.51 (br, 2H, —C4H4—NH2), 3.26 (br, 4H, piperidinyl), 2.57 (dd, J=10.2 and 14.1 Hz, 1H, —CO—CH2), 2.31 (dd, J=5.4 and 14.1 Hz, 1H, —CO—CH2—), 1.43 (br, 2H, piperidinyl), 1.26 (br, 4H, piperidinyl); 13C NMR (75 MHz, CDCl3) δ 169.7, 153.3, 145.7, 145.2, 141.0, 129.5, 129.2, 128.2, 128.1, 126.7, 124.8, 124.6, 123.2, 123.1, 121.5, 115.0, 61.2, 47.6, 43.2, 41.7, 24.8, 24.2; HRMS (FAB, M+H) Calcd for C28H32N5O 454.2607, found 454.2654.

EXAMPLE 8 Preparation of 4-{N-[4-(4-fluorobenzenesulfonylamido)benzyl]acetamido}-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline (10: KYS05042)

The compound (9) (0.11 g, 0.26 mmol) was dissolved in 10 ml of dichloromethane and pyridine (0.06 g, 0.76 mmol) was added thereto. 4-fluorobenzenesulfonyl chloride (0.06 g, 0.31 mmol) dissolved in 5 in 5 ml of dichloromethane at 0° C. was gently dropped to the reaction mixture and stirred for 24 hours at a room temperature. After the reaction was completed, the reaction mixture was extracted with dichloromethane three times and washed with brine. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The reaction mixture was subjected to column chromatography (CH2Cl2:MeOH=10:1) to purify the title compound in the form of a white crystal (10) (0.11 g, 73%).

1H NMR (300 MHz, CDCl3) δ 7.66-7.62 (m, 2H, aromatic), 7.28-7.23 (m, 2H, aromatic), 7.20-7.06 (m, 9H, aromatic), 7.04-6.90 (m, 4H, aromatic), 6.72 (br, 1H, —CO—NH—CH2—), 5.19 (dd, J=6.0 and 9.9 Hz, 1H, —CH2—CH—N—), 4.41 (dd, J=6.1 and 14.8 Hz, —NH—CH2—), 4.24 (dd, J=5.5 and 14.8 Hz, —NH—CH2—), 3.28 (br, 4H, piperidinyl), 2.74 (dd, J=9.6 Hz and 14.1 Hz, 1H, —CO—CH2), 2.44 (dd, J=6.0 and 14.1 Hz, 1H, —CO—CH2—), 1.39 (br, 2H, piperidinyl), 1.25(br, 4H, piperidinyl); 13C NMR (75 MHz, CDCl3) δ 170.1, 166.7, 153.9, 145.3, 141.7, 135.9, 135.0, 129.9, 129.7, 129.3, 128.9, 128.4, 126.7, 125.2, 124.8, 123.2, 121.5, 116.3, 116.0, 61.4, 47.9, 43.3, 42.0, 25.2, 24.6; HRMS (FAB, M+H) Calcd for C34H35FN5O3S 612.2445, found 612.2436.

The physicochemical properties of the compounds prepared in Examples 3 to 8 are shown in Table 1, which is provided below.

TABLE 1 Structure of No. compound Physicochemical properties 1 1H NMR(300 MHz, CDCl3) δ7.24-7.18(m, 4H, aromatic), 7.08-7.00(m, 3H, aromatic), 6.92-6.89(m, 2H, aromatic), 5.08(dd, J=4.8 and 10.4 Hz, 1H, —CH2—CH—N—), 3.69(s, 3H, —OCH3), 3.55-3.43(m, 8H, morpholinyl), 2.80(dd, J=10.4 and 15.0 Hz, 1H, —CO—CH2—), 2.50(dd, J=4.8 and 15.0 Hz, # 1H, —CO—CH2—); 13C NMR(75 MHz, CDCl3) # δ172.0, 153.0, 145.8, 143.7, 129.6, 128.7, 126.1, 125.0, 124.5, 123.2. 123.1, 122.5, 66.6, 61.2. 52.1, 46.4, 40.0. 2 1H NMR(300 MHz, CDCl3) δ7.15-7.10(m, 4H, aromatic), 6.98(d, J=7.8 Hz, 2H, aromatic), 6.91 Ct, J=7.2 Hz. 1H, aromatic), 685-6.80(m, 2H, aromatic), 5.01(dd, J=4.5 and 10.2 Hz, 1H, —CH2—CH—N—), 3.62(s, 3H, —OCH3), 3.38 (s, 4H, piperazinyl), 2.73(dd, J=10.2 and 15.0 Hz, 1H, —CO—CH2—), 2.42(dd, # J=4.5 and 15.0 Hz, 1H, —CO—CH2—), 2.18-2.12(m, 7H, 1-methyl- # piperazinyl); 13C NMR(75 MHz, CDCl3) δ172.0, 152.9, 145.9, 143.9, 129.5, 128.6, # 126.0, 124.9, 124.3, 123.1, 122.9, 122.5, 61.2, 54.7, 52.0, 46.3, 45.8, 39.9. 3 mp 131° C.; 1H NMR(300 MHz, CDCl3) δ7.14(m, 1H, aromatic), 7.03(m, 1H, aromatic), 6.98(m, 1H, aromatic), 6.90(m, 1H, aromatic), 4.67(dd, J=5.1 and 9.6 Hz, 1H, —CH2—CH—N—). 3.62(s, 3H, —OCH3). 3.42—3.36(m, 2H, piperidinyl), 3.19(m, 1H, piperidinyl), 3.10(br, 1H, —N—OH—), 2.48(dd, J= # 9.6 and 14.4 Hz, 1H, —CO—CH2—), 2.31(dd, J=5.4 and 14.4 Hz, 1H, —CO—CH2), # 1.87-1.47(m, 12H, piperidinyl and cyclohexyl), 1.25-1.01(m, 5H, piperi- # dinyl and cyclohexyl); 13C NMR(75 MHz, CDCl3) δ171.9. 157.9, 144.9, 128.2, # 128.0, 124.1, 123.0, 122.6, 61.4, 51.7, 51.5, 47.7, 32.7, 31.4, 26.8, 26.5, 25.6, 25.3. 4 1H NMR(300 MHz, CDCl3) δ7.19(m, 1H, aromatic), 7.08(m, 1H, aromatic), 7.04(m, 1H, aromatic), 6.98(m, 1H, aromatic), 4.72(dd, J=5.4 and 9.8 Hz, 1H, —CH2CH—N—), 3.72(m, 4H, morpholinyl), 3.65(s, 3H, —OCH3), 3.50(m, 4H, morpholinyl), 3.24(m, 1H, —N—CH—), 2.51(dd, J=9.9 and 13.8 Hz, # 1H, —CO—CH2—), 2.35(dd, J=5.1 and 13.8 Hz, 1H, —CO—CH2—), 1.88(m, # 1H, piperidinyl), 1.74(m, 1H, piperidinyl), 1.63-1.55(m, 3H, piperi- # dinyl), 1.29-1.05(m, 5H, piperidinyl); —C NMR(75 MHz, CDCl3) δ172.2, 157.4, # 144.1, 128.3, 127.8, 124.2, 123.3, 123.1, 67.1, 61.4, 51.8, 51.5, 40.8, 32.7, 31.4, 26.7, 26.4, 25.5. 5 1H NMR(300 MHz, CDCl3) δ7.18(m, 1H, aromatic), 7.07(m, 1H, aromatic), 7.02(m, 1H, aromatic), 6.96(m, 1H, aromatic), 4.71(dd, J=5.1 and 9.5 Hz, 1H, # —CH2—CH—N—), 3.65(s, 3H, —OCH3), 3.58(br, 1H, —N—CH—), # 3.43(br, 2H, piperazinyl), 3.27-3.23(m, 2H, piperaziny), 2.63(br, 2H, piperaziny), # 2.50(dd, J=9.6 and 14.0 Hz, 1H, —CO—CH2—), 2.37-2.26(m, 6H, # —CO—CH2—, piperazinyl, and —N—CH3), 1.89-1.76(m, 2H, cyclohexyl), 1.60-1.54(m, 3H, # cyclohexyl), 1.29-1.04(m, 5H, cyclohexyl); 13C NMR(75 MHz, CDCl3) δ # 171.7, 157.4, 144.5, 128.2, 127.9, 124.1. 123.1, 123.0, 61.4, 55.3, 51.7, 51.5, 46.5, 40.7, 32.7, 31.4, 26.7, 26.4, 25.6. 6 mp 96° C.; 1H NMR(300 MHz, CDCl3) δ7.16(m, 1H, aromatic), 7.07(m, 1H, aromatic), 7.01(m, 1H, aromatic), 6.93(m, 1H, aromatic), 4.69(dd, J=5.4 and 9.5 Hz, 1H, —CH2—CH—N—), 3.71(sept, J=7.2 Hz, 1H, —N—CH—(CH3)2), 3.65(s, 3H, —OCH3), 3.44-3.84(m, 3H, piperidinyl), 3.13(br, 1H, piperidinyl), # 2.51(dd, J=9.6 and 13.8 Hz, 1H, —CO—CH2—), 2.35(dd, J=5.4 and 14.1 Hz, 1H, —CO—CH2—), 1.54(br, 6H, piperidinyl), 1.22(d, J=7.2 Hz, 3H, —N—CH—(CH3)2, 0.78(d, J=6.9 Hz, 3H, —N—CH—(CH3)2); 13C NMR(75 MHz, CDCl3) δ171.7, # 157.8, 144.7, 128.1, 127.9, 124.0, 123.0, 122.7, 52.4, 51.6, 50.3, 40.6, 26.1, 25.2, 21.9, 20.7. 7 1H NMR(300 MHz, CDCl3) δ7.11(m, 1H, aromatic), 7.01(m, 1H, aromatic), 6.97(m, 1H, aromatic), 6.90(m, 1H, aromatic), 4.65(dd, J=5.1 and 9.6 Hz, 1H, —CH2CH—N—), 3.73-3.64(m, 5H, —N—CH—(CH3)2 and morpholinyl), 3.58 (s, 3H, —OCH3), 3.44(br, 4H, morpholinyl), 2.44(dd, J=9.9 and 13.8 Hz, 1H, # —CO—CH2—), 2.30(dd, J=5.1 and 14.1 Hz, 1H, —CO—CH2—), 1.15(d, J=6.6 Hz, # 3H, 0.73(d, J=6.0 Hz, 3H, —N—CH—(CH3)2); 13C NMR(75 MHz, CDCl3) δ171.4, 157.3, 144.1, 128.3, 127.8, 124.1, 123.3, 123.1, 67.0, 52.4, 51.7, 50.3, 40.7, 21.9, 20.7, 8 1H NMR(300 MHz, CDCl3) δ7.09(m, 1H, aromatic), 7.01(m, 1H, aromatic), 6.94(m, 1H, aromatic), 6.87(m, 1H, aromatic), 4.62(dd, J=5.1 and 9.6 Hz, 1H, —CH2CH—N—), 3.65(sept, J=6.6 Hz, 1H, —N—CH—(CH3)2), 3.56(s, 3H, —OCH3), 3.40(br, 4H, piperazinyl), 2.46(br, 4H, piperazinyl), 2.42(dd, J= # 9.3 and 14.4 Hz, 1H, —CO—CH2—), 2.31-2.25(m, 4H, —CO—CH2—and —N—CH3),1.14 (d, J=6.6 Hz, 3H, —N—CH—(CH3)2), 0.71(d, J=6.6 Hz, 3H, —N—CH—(CH3)2); # 13C NMR(75 MHz, CDCl3) δ171.5, 157.2, 144.0, 128.3, 127.8. 124.1, 123.1. 123.0, 55.2, 52.5, 51.7, 5.03, 46.4, 40.7, 21.9, 20.7. 9 1H NMR(300 MHz, CDCl3) δ7.26-7.18(m, 4H, aromatic), 7.04-6.99(m, 3H, aromatic), 6.94-6.88(m, 2H, aromatic), 5.10(dd, J=4.6 and 10.7 Hz, 1H, —CH2—CH—N—), 3.75(s, 3H, —OCH3), 2.88(s, 6H, —N—Me2), 2.83(dd, J=10.7 and 15.1 Hz, 1H, —CO—CH2—), 2.50(dd, J=4.5 and 15.0 Hz, 1H —CO—CH2—); # 13C NMR(75 MHz, CDCl3) δ171.9, 153.5, 145.8, 144.0, 129.3, 128.3, 125.3, 124.7, 123.8, 122.8, 122.0, 121.8, 61.2, 51.8, 39.7, 37.6. 10 1H NMR(300 MHz, CDCl3) δ7.16(m, 1H, aromatic), 7.21-7.09(m, 2H, aromatic), 7.02-6.91(m, 2H, aromatic), 4.62(dd, J=4.5 and 10.2 Hz, 1H, —N—CH2—CH—N—), 3.67(s, 3H, —OCH3), 3.36-3.27(m, 5H, piperidinyl and —N—CH2CH3), 3.08(m, 1H, —N—CH2CH3), 2.61(dd, J=9.9 and 14.7 Hz, # 1H, —CO—CH2—), 2.34(dd, J=4.6 and 15.1 Hz, 1H, —CO—CH2—), 1.63(br, 6H, piperidinyl), 1.00(t, J=7.2 Hz, 3H, —N—CH2—CH3); 13C NMR(75 MHz, CDCl3) δ171.7, 157.2, 144.4, 128.0, 126.3, 124.1, 122.7, 122.4, 55.3, 51.4, 47.2, 39.9, 25.8, 24.8, 14.0. 11 1H NMR(300 MHz, CDCl3) δ7.21-7.11(m, 2H, aromatic), 7.02-6.91(m, 2H, aromatic), 4.61(dd, J=4.8 and 10.5 Hz, 1H, —CH2—CH—N—), 3.67(s, 3H, —OCH3), 3.21(m, 1H, 3.13 —N—CH2—CH3), 3.03(m, 1H, —N—CH2—CH3), 2.96 (s, 6H, —NMe2), 2.59(dd, J=9.9 and 14.7 Hz, 1H, —CO—CH2—), 2.34(dd, # J=4.7 and 15.1 Hz, 1H, —CO—CH2—), 1.00(t, J=7.2 Hz, 3H, —N—CH2—CH3); # 13C NMR(75 MHz, CDCl3) δ171.5, 157.4, 144.1, 128.0, 125.7, 124.2, 122.5, 122.2, 55.5, 51.3, 46.9, 39.9, 38.4, 13.8. 12 mp 237° C.; 1H NMR(300 MHz, DMSO) δ7.59(d, J=7.8 Hz, 1H aromatic), 7.48-7.39(m, 5H, aromatic), 7.31-7.31(m, 2H, aromatic), 7.21(m, 1H, aromatic), 5.32(dd, J=6.3 and 8.2 Hz, 1H, —CH2—C+EE,uns H—N—), 3.60-3.48(m, 4H, morpholinyl), 3.40-3.33(m, 4H, morpholinyl), 2.98(dd, J=8.2 and 15.6 # Hz, 1H, —CO—CH2—), 2.72(dd, J=6.3 and 15.1 Hz, 1H, —CO—CH2—); 13C NMR(75 MHz, DMSO) δ175.8, 157.1, 147.0, 136.1, 134.4, 133.5, 131.9, 130.7, 130.2, 129.9, 128.4, 122.0, 69.3, 65.6, 52.7, 50.9, 44.0. 13 1H NMR(300 MHz, CD3OD) δ7.31-7.15(m, 7H, aromatic), 7.10-7.08(m, 2H, aromatic), 5.11(dd, J=5.4 and 9.8 Hz, 1H, —CH2—CH—N—), 3.39-3.32(m, 4H, piperazinyl), 2.57-2.31(m, 6H, —CO—CH2—, and piperazinyl), 2.24(s, 3H, —N—CH3); 13C NMR(75 MHz, CD3OD) δ175.6, 153.2, 144.0, 135.4, # 129.9, 128.8, 127.6, 126.8, 125.6, 125.4, 124.2, 119.1, 63.0, 53.2, 46.7, 44.2, 43.2. 14 mp 245° C.; 1H NMR(300 MHz, DMSO) δ7.73-7.71(m, 2H, aromatic), 7.39-7.28 (m, 5H, aromatic), 7.22-7.13(m, 4H, aromatic), 7.03-6.94(m, 3H, aromatic), 5.35 (dd, J=6.7 and 8.4 Hz, 1H, —CO—CH2—), 2.75(dd, J=8.3 and 14.9 Hz, 1H, —CO—CH2—), 2.54(dd, J=6.2 and 14.9 Hz, 1H, —CO—CH2—); 13C NMR(75 # MHz, DMSO) δ172.3, 154.7, 145.7, 142.1, 136.3, 130.9, 130.1, 129.7, 129.0, 128.9, 127.4, 126.7, 126.1, 124.8, 124.6, 123.8, 59.3, 41.2. 15 1H NMR(300 MHz, CDCl3) δ7.73(d, J=8.1 Hz, 1H, aromatic), 7.38-7.33(m, 2H, aromatic), 7.27-7.21(m, 4H, aromatic), 7.12(d, J=3.9 Hz, 2H, aromatic), 5.23(dd, J=4.8 and 9.3 Hz, 1H, —CH2—CH—N—), 2.97(s, 6H, —N—Me2), 2.83 (dd, J=9.3 and 14.4 Hz, 1H, —CO—CH2—), 2.60(dd, J=4.9 and 14.3 Hz, 1H —CO—CH2). 16 1H NMR(300 MHz, CDCl3) δ7.28(d, J=7.8 Hz, 1H, aromatic), 7.20-7.15(m, 2H, aromatic), 7.08(m, 1H, aromatic), 4.94(dd, J=6.0 and 8.7 Hz, 1H, —CH2—CH—N—), 3.51(m, 1H, —N—CH2—CH3), 3.38-3.25(m, 5H, piperidinyl and —N—CH2—CH3), 2.42(dd, J=8.8 and 14.8 Hz, 1H, —CO—CH2—), 2.22(dd, J= # 5.6 and 14.8 Hz, 1H, —CO—CH2—), 1.49(br, 6H, piperidinyl), 1.09(t, J=7.2 Hz, 3H, —N—CH2—CH3). 17 1H NMR(300 MHz, CDCl3 and CD3OD) δ7.42(d, J=7.8 Hz, 1H, aromatic), 7.30-7.26(m, 2H, aromatic), 7.18(m, 1H, aromatic), 5.00(dd, 15.1 and 9.6 Hz, 1H, —CH2—CH—N—), 3.65-3.41(m, 2H, —N—CH2—CH3), 3.17(s, 6H, —NMe2), 2.54(dd, J=9.6 and 15.0 Hz, 1H, —CO—CH2—), 2.41(dd, J=5.4 and # 14.7 Hz, 1H, —CO—CH2—), 1.16(t, J=7.2 Hz, 3H, —N—CH2CH3). 18 mp 168° C.; 1H NMR(300 MHz, CDCl3) δ7.71(br, 1H, —CO—NH—CH2—Ph), 7.35-7.31(m, 2H, aromatic), 7.29-7.19(m, 5H, aromatic), 7.16-7.03(m, 5H, aromatic), 6.96-6.92(m, 2H, aromatic), 5.18(dd, J=5.0 and 10.1 Hz, 1H, —CH2—CH—N—), 4.53(dd, J=6.0 and 14.4 Hz, 1H, —NH—CH2—Ph), 4.42(dd, J= # 6.3 and 14.4 Hz, 1H, —NH—CH2—Ph), 3.17(br, 4H, piperidinyl, 2.68(dd, J=10.1 and 14.0 Hz, 1H, —CO—CH2—), 2.23(dd, J=5.0 and 14.1 Hz, 1H, # —CO—CH2—), 1.37-1.33(m, 2H, piperidinyl), 1.18(br, 4H, piperidiny); 13C NMR (75 MHz, CDCl3) δ170.4. 153.9, 146.1, 143.2, 138.6, 129.3, 128.8, 128.5, 128.4, 127.7, 127.0, 125.2, 124.9, 124.4, 123.2, 122.8, 122.3, 61.1, 47.4, 43.9, 41.9, 25.3, 24.7; HRMS(FAB, M + H)Calcd for C28H31N4O 439.2498, found 439.2534. 19 mp 138° C.; 1H NMR(300 MHz, CDCl3 and CD3OD) δ7.91(br, 1H, —NH—Bn), 7.31-7.19(m, 8H, aromatic), 7.12-7.05(m, 4H, aromatic), 7.01-6.93(m, 2H, aromatic), 5.18(dd, J=4.8 and 10.8 Hz, 1H, —CH2—CH—N—), 4.48(dd, J=5.5 and 14.2 Hz, 1H, —NH—CH2—Ph), 4.32(dd, J=5.5 and 14.2 Hz, 1H, —NH—CH213 Ph), # 3.37-3.21(m, 8H, morpholinyl), 2.53(dd, J=10.5 and 14.1 Hz, 1H, —CO—CH2—), 2.36(dd, J=4.6 and 13.9 Hz, 1H, —CO—CH2—); 130 NMR(75 MHz, CDCl3) δ170.6. 154.1, 145.3, 142.9, 138.4, 129.5, 128.8, 128.5, 127.7, 127.2, 125.1, 124.9, 123.5, 123.1, 122.5, 66.2, 61.4, 46.5, 44.0, 41.7; HRMS(FAB, M + H) Calcd for C27H28N4O2 441.2291, found 441.2290. 20 mp 186° C.; 1H NMR(300 MHz, CDCl3) δ7.28-7.19(m, 7H, aromatic), 7.17-7.11 (m, 3H, aromatic), 7.09-7.01(m, 2H, aromatic), 6.96-6.87(m, 2H, aromatic), 6.68 (t, J=5.4 Hz, 1H, —CO—NH—CH2—Ph), 5.20(dd, J=5.4 and 9.3 Hz, 1H —CH2—CH—N—), 4.50(dd, J=5.8 and 14.5 Hz, 1H, —NH—CH2—Ph), 4.42(dd, # J=5.8 and 14.5 Hz, 1H, —NH—CH2—Ph), 3.27(br, 4H, piperazinyl), # 2.55(dd, J=9.6 and 14.1 Hz, 1H, —CO—CH2—), 2.34(dd, J=5.7 and 14.4 Hz, 1H, —CO—CH2—), 2.14(s, 3H, —N—CH3), 2.11-2.04(m, 4H, piperazinyl); 13C NMR(75 MHz, CDCl3) δ170.2, 153.5, 145.8, 143.4, 138.3, 129.4, 128.9, 128.5, 128.4, 127.8, 126.7, 125.2, 124.6, 123.1, 123.0, 122.7, 61.2, 54.4, 46.3, 46.1, 44.0, 42.1; HRMS(FAB, M + H) # Calcd for C28H32N5O 454.2607, found 454.2600. 21 mp 204° C.; 1H NMR(300 MHz, DMSO) δ8.61(t, J=5.1 Hz, 1H, —NH—CH2—Ph), 7.68(d, J=7.2 Hz, 2H, aromatic), 7.40-7.20(m, 9H, aromatic), 7.17-7.10(m, 4H, aromatic), 7.04-6.92(m, 3H, aromatic), 5.39(dd, J=5.4 and 8.4 Hz, 1H, —CH2—CH—N—), 4.41(dd, J=5.4 and 14.7 Hz, 1H, —NH—CH2—Ph), 4.30(dd, J= # 5.1 and 15.0 Hz, —NH—CH2—Ph), 2.77(dd, J=9.0 and 13.8 Hz, 1H, —CO—CH2—), 2.43 (dd, J=5.3 and 14.2 Hz, 1H, —CO—CH2—); 13C NMR(75 MHz, DMSO)δ169.7, # 154.8, 145.9, 142.3, 139.8, 136.7, 130.7, 130.3, 129.5, 129.0, 128.8, 128.4, 127.9, 127.6, 126.6, 126.0, 124.8, 124.4, 123.9, 59.9, 43.1, 42.3, 22 1H NMR(300 MHz, CDCl3) δ7.36-7.30(m, 5H, aromatic). 7.20-7.15(m, 4H, aromatic), 7.02-6.97(m, 3H, aromatic), 6.91-6.87(m, 2H, aromatic), 5.18(s, 2H, —O—CH2—Ph), 5.07(dd, J=4.8 and 10.2 Hz, 1H, —CH2—CH—N—), 3.31(br, 4H, piperidinyl), 2.84(dd, J=10.5 and 15.3 Hz, 1H, —CO—CH2—), 2.52(dd, J= # 4.7 and 14.9 Hz, 1H, —CO—CH2—), 1.45-1.40(m, 2H, piperidinyl), 1.30-1.21 (m, 4H, piperidinyl); 13C NMR(75 MHz, CDCl3) δ171.5, 153.5, 146.2, 144.2, 135.8, 129.4, 128.9, 128.7, 128.6, 127.2, 126.1, 125.0, 124.2, 123.0, 122.8, 122.5, 66.9, 61.2, 47.1, 40.0, 25.6, 25.0. 23 1H NMR(300 MHz, CDCl3) δ7.37-7.31(m, 5H, aromatic), 7.23-7.17(m, 4H, aromatic), 7.04-6.99(m, 3H, aromatic), 6.92-6.90(m, 2H, aromatic), 5.23(d, J=12.3 Hz, —O—CH2—Ph), 5.12(d, J=12.3 Hz, —O—CH2—Ph), 5.07(dd, J=4.4 and 10.7 Hz, 1H, —CH2—CH—N—), 3.42-3.30(m, 8H, morpholinyl), 2.81d(dd, # J=10.5 and 150 Hz, 1H, —CO—(75 MHz, CDCl3) δ171.4, 153.2, 145.7, 143.6, 135.7, 129.5, 129.1, 128.9, 128.7, 127.7, 127.2, 126.1, 125.0, 124.6, 123.2, 122.6, 66.5, 65.2, 61.3, 46.4, 40.2. 24 1H NMR(300 MHz, CDCl3) δ7.36-7.31(m, 5H, aromatic), 7.22-7.15(m, 4H, aromatic), 7.03-7.00(m, 3H, aromatic), 6.93-6.89(m, 2H, aromatic), 5.21(d, J=12.0 Hz 1H, —O—CH2—Ph), 5.15(d, J=12.3 Hz, 1H, —O—CH2—Ph), 5.08(dd, J=4.8 and 10.2 Hz, 1H, —CH2—CH—N—), 3.27(br, 4H, piperazinyl), 2.86(dd, J=10.5 # and 150 Hz, 1H, —CO—CH2—3H, —N—CH3), 2.14(br, 4H, piperazinyl); 13C NMR(75 MHz, CDCl3) δ171.4, 153.0, 145.9, 143.9, 135.7, 129.4, 129.0, 128.9, 128.8, 128.7, 126.0, 125.0, 124.4, 123.2, 122.8, 122.6, 67.0, 61.2, 54.7, 46.3, 45.8, 40.1. 25 1H NMR(300 MHz, CDCl3) δ7.71-7.68(m, 2H, aromatic), 7.50(d, J=7.2 Hz, 1H, aromatic), 7.34-7.15(m, 9H, aromatic), 7.13-7.03(m, 4H, aromatic), 7.01-6.92 (m, 3H, aromatic), 5.39(dd, J=6.3 and 7.8 Hz, 1H, —CH2—CH—N—), 5.22(d, J=12.3 Hz, 1H, —CH2—Ph), 5.13(d, J=12.0 Hz, 1H, —O—CH2—Ph), 2.95(dd, J=8.1 and 15.0 Hz, 1H, —CO—CH2 # NMR(75 MHz, CDCl3) δ171.0, 155.0, 145.4, 142.1, 136.3, 135.7, 130.4, 130.0, 129.2, 128.9, 128.8, 128.7, 128.5, 126.4, 125.3, 125.1, 124.4, 123.7, 67.1, 59.5, 41.0. 26 1H NMR(300 MHz, CDCl3 and CD3OD) δ8.14-8.10(m, 2H, aromatic), 7.39(d, J=8.7 Hz, 2H, aromatic), 7.30-7.13(m, 4H, aromatic), 7.08-7.03(m, 3H, aromatic), 6.98-6.89(m, 2H, aromatic), 5.20(dd, J=6.0 and 9.3 Hz, 1H, —CH2—CH—N—), 4.59 (d, J=15.6 Hz, 1H, —NH—CH2—), 4.36(d, J=15.3 Hz, 1H,—NH—CH2—), 2.78(s, 6H, —NMe2), # 121.9, 61.1, 42.7, 41.2, 37.8. 27 1H NMR(300 MHz, CDCl3)δ9.19(t, J=5.4 Hz, 1H, —CO—NH—CH2—), 8.11(d, J=8.7 Hz, 2H, —C4H4—NO2), 7.57(d, J=9.0 Hz, 2H, # —CH2—C4H4—NO2), 7.18-7.07 (m, 4H, aromatic), 4.89(dd, J=4.1 and 10.7 Hz, 1H, —CH2—C—N—), 4.49(dd, J=4.7 and 13.4 Hz, 1H, —NH—C2—), 4.43(dd, J=4.7 Hz and 13.4 Hz, 1H —NH—C # 14.8 Hz, 1H, —CO—CH2), 2.08(dd, J=4.1 and 14.6 Hz, 1H, —CO—CH2—), 1.52(br, 6H, piperidinyl), 1.07(t, J=7.2 Hz, 3H —N—CH2CH3); 13C NMR(75 MHz, CDCl3) δ177.3, 170.1, 156.7, 146.3, 138.4, 128.6, 128.5, 127.2, 124.4, 124.3, 123.5, 120.2, # 55.1, 47.5, 42.6, 41.2, 25.3, 24.1, 23.3, 14.2. 28 1H NMR(300 MHz, CDCl3) δ9.26(t, J=6.0 Hz, 1H, —CO—NH—CH2—), 8.12(d, J=8.7 Hz, 2R, aromatic), 7.62-7.55(m, 3H, aromatic), 7.17-7.09(m, 3H, aromatic), 4.85(dd, J=4.2 and 10.8 Hz, 1H, —CH2CH—N—), 4.49-4.46(m, 2H, ——NH—C2—), 3.28-3.22(m, 2H, —N—C2CH3), 3.05(s, 6H, —NMe2), 2.83(dd, J=10.9 and 14.3 Hz, 1H, —CO— # Hz, 3H, —N—CH2CH3); 13C NMR(75 MHz, CDCl3) δ169.6, 155.9 147.0 146.3, 134.3, 129.1, 128.6, 126.4, 125.7, 124.4, 123.4, 119.1, 55.9, 48.1, 42.6, 41.3, 40.6, 14.0. 29 1H NMR(300 MHz, CDCl3) δ7.35(t, J=5.6 Hz, 1H, —CO—NH—CH2), 7.26-7.20 (m, 2H, aromatic), 7.14-6.99(m, 6H, aromatic), 6.92-6.83(m, 2H, aromatic), 6.57-6.54(m, 2H, aromatic), 5.20(dd, J=5.1 and 9.9 Hz, 1H, —CH2—CH—N—), 4.41 (dd, J=5.6 and 14.3 Hz, 1H, —NH—CH2—), 4.32(dd, J=5.6 and 14.3 Hz, 1H —NH—CH2—), # 14.4 Hz, 1H, —CO—CH2), 2.25(dd, J=5.1 and 14.1 Hz, 1H, —CO—CH2—); 13C NMR (75 MHz, CDCl3) δ170.0, 153.9, 145.7, 145.6, 143.1, 129.4, 129.2, 128.0, 126.2, # 124.9, 123.9, 122.3, 122.2, 121.9, 115.0, 61.2, 43.3, 41.6, 37.9, 30 1H NMR(300 MHz, CDCl3) δ8.24(br, 1H O═C—NH—CH2—), 7.08-7.03(m, 3H, aromatic), 6.97-6.84(m, 3H, aromatic), 6.57(d, J=8.1 Hz, 2H, —CH2—C4H4—NO2), 4.78(dd, J=5.6 and 8.9 Hz, 1H, —CH2—CH—N—), 4.37(dd, J=6.1 and 14.3 Hz, 1H, —NH—CH2—), 4.24(dd, J=5.6 Hz and 14.3 Hz, 1H, # —NH—CH2—), 3.27(m, 1H, —N—CH2CH3), 3.18-3.01(m, 5H, piperidinyl and —N—CH2CH3), 2.26(dd, J=9.4 and 14.3 Hz, 1H, —CO—CH2), 2.01(dd, J=5.6 and 14.3 Hz, 1H, —CO—CH2—), 1.43(br, 6H, piperidinyl, 0.98(t, J=6.9 Hz, 3H —N—CH2CH3); 13C NMR(75 MHz, CDCl3) δ # 169.5, 157.0, 145.3, 142.0, 129.0, 128.1, 127.4, 127.0, 123.9, 122.6, 121.1, 114.5, 76.4, 54.6, 46.8, 42.6, 41.3, 25.2, 24.1, 13.9. 31 1H NMR(300 MHz, CDCl3) δ8.13(br, 1H, —CO—NH—CH2—), 7.14-7.07(m, 4H, aromatic), 6.97(dd, J=4.1 Hz, 2H, aromatic), 6.50(d, J=8.3 Hz, 2H, aromatic), 4.78(dd, J=4.4 and 10.7 Hz, 1H, —CH2—CH—N—), 4.36(dd, J=6.2 and 14.1 Hz, 1H, —CO—NH—CH2—), 4.19(dd, J=5.5 and 14.1 Hz, 1H, —CO—NH—CH2—), # 3.19-3.13(m, Hz, 1H, —CO—CH2), 2.02(dd, J=4.4 and 14.2 Hz, 1H, —CO—CH2—), 0.98(t, J=7.1 Hz, 3H, —N—CH2CH3). 32 1H NMR(300 MHz, CDCl3) δ7.66(d, J=8.4 Hz, 1H, aromatic), 7.58-7.73(m, 3H, aromatic), 7.28-7.21(m, 3H, aromatic), 7.18-6.95(m, 12H, aromatic), 5.19(dd, J=5.2 and 10.1 Hz, 1H, —CH2CH—N—), 4.35(dd, J=6.1 and 14.2 Hz, 1H, —NH—CH2—), 4.24(dd, J=5.5 and 14.8 Hz, 1H, —NH—CH2—), 3.28(br, 4H, piperidinyl), 2.82(dd, J=10.5 and 14.4 Hz, # 1H, 14.0 Hz, 1H, —CO—CH2—), 2.29(s, 3H, —SO2—C4H4—CH3), 1.33(br, 2H, piperidinyl), 1.20(br, 4H, piperidinyl); 13C NMR(75 MHz, CDCl3) δ170.4, 154.0, 144.9, 143.6, 138.9, 136.9, 136.7, 134.7, 129.8, 129.2, 129.0, 128.9, 127.3, 126.2, 125.9, 125.4, # 124.4, 124.0, 121.1, 121.0, 61.7, 48.6, 43.2, 41.9, 24.8, 24.2, 21.7; HRMS(FAB, M + H) Calcd for C35H38N5O3S 608.2695, found 608.2680. 33 1H NMR(300 MHz, DMSO) δ10.2(br, 1H, Ts—NH—), 8.52(t, J=5.6 Hz, 1H, —CO—NH—CH2), 7.62(d, J=8.1 Hz, 2H, aromatic), 7.33-7.23(m, 4H, aromatic), 7.15-7.05(m, 3H, aromatic), 7.01-6.96(m, 7H, aromatic), 6.82(m, 1H, aromatic), 5.08(dd, J=4.4 and 10.4 Hz, 1H, —CH2—CH—N—), 4.26(dd, J=6.0 and 14.7 # Hz, 1H, —NH—CH2—), 4.17(dd, J=5.6 and 14.8 Hz, 1H, —NH—CH2—), 2.63(s, 6H, # —NMe2), 2.52(m, 1H, —CO—CH2), 2.33(s, 3H, —SO2—C4H4—CH3), # 2.24(dd, J=4.1 and 14.0 Hz, 1H, —CO—CH2—); 13C NMR(75 MHz, DM50) δ169.4, 152.9, # 145.8, 143.9, 143.1, 136.7, 136.4, 134.8, 129.6, 129.2, 128.5, 127.7, 126.6, 126.2, 124.8, 123.2, 122.0, 121.5, 121.1, 119,7. 60.8, 41.7, 40.8, 37.2, 20.9. 34 1H NMR(300 MHz, CDCl3) δ8.28(t, J=5.5 Hz, 1H, —CO—NH—CH2—), 7.72(d, J=8.4 Hz, 2H, aromatic), 7.63(d, 17.8 Hz, 1H, aromatic), 7.18-7.02(m, 9H, aromatic), 4.99(dd, J=5.0 and 10.4 Hz, 1H, —CH2CH—N—), 4.22(m, 2H, —NH—CH2—), 3.38-3.22(m, 6H, piperidinyl and —N—CH2CH3), 2.83(dd, J=10.5 and 14.1 Hz, 1H, —CO # Hz, 1H, —CO—CH2—), 1.45(br, 6H, piperidinyl), 1.09(t, J=7.0 Hz, 3H —N—CH2CH3); 13C NMR(75 MHz, CDCl3) δ169.3, 155.2, 143.3, 136.5, 136.4, 134.5, 133.8, 129.4, 128.8, 127.2, 126.4, 125.9, 124.4, 120.8, 119.1, 77.2, 55.4, 48.2, 42.6, 41.3, 25.1, 23.5, 21.4, 14.1. 35 1H NMR(300 MHz, CDCl3) δ8.51(br, 1H, —CO—NH—CH2—), 7.68(d, J=8.1 Hz, 2H, aromatic), 7.56(d, J=7.2 Hz, 1H, aromatic), 7.11-6.94(m, 9H, aromatic), 4.85(m, 1H, —CH2—CH—N—), 4.31-4.00(m, 2H, —CO—NH—CH3—), 3.02-3.00(m, 2H, —N—C2CH3), 2.73(s, 6H, —NMe21), 2.76(m, 1H, —CO—CH2), 2.17(s, 3H, —SO # 13C NMR(75 MHz, CDCl3) δ169.0. 155.1, 143.0, 136.3, 134.5, 132.7, 129.2, 129.0, 128.5, 127.0, 126.0, 125.7, 124.2, 120.6, 118.5, 55.6, 47.9, 42.4, 41.2, 40.3, 21.1, 13.7. 36 1H NMR(300 MHz, DMSO)δ10.3(br, 1H, Ts—NH—), 8.56(t, J=5.3Hz, 1H —CO—NH—CH2), 7.82-7.77(m, 2H, aromatic), 7.41-7.35(m, 2H, aromatic), 7.30-7.25(m, 2H, aromatic), 7.19-6.98(m, 10H, aromatic), 6.89(m, 1H, aromatic), 5.10(dd, J=3.9 and 10.5Hz, 1H, —CH2—CH—N—), 4.26(dd, J=5.2 and 14.5 Hz, 1H, —NH—CH2—), 4.17(dd, J 4.8 and 14.4 Hz, 1H, # 6H, —NMe2), 2.55(m, 1H, —CO—CH2), 2.27(dd, J=3.9 and 14.4 Hz, 1H, —CO—CH2—); 13C NMR(75 MHz, DMSO) δ169.3, 165.9, 162.6, 152.9, 145.4, 136.1, 135.9, 135.2, 129.8, 129.6, 129.3, 128.6, 127.9, 126.2, 125.0, 123.7, 121.4, 120.2, # 116.6, 116.3, 60.9, 41.8, 40.9, 37.5, 37 1H NMR(300 MHz, CDCl3)δ8.38(br, 1H, —CO—NH—CH2—), 7.89-7.84(m, 2H, aromatic), 7.56(d, J=8.4Hz, 1H, aromatic), 7.14-7.05(m, 7H, aromatic), 7.01-6.95(m, 2H, aromatic), 4.94(dd, J=5.2 and 10.0 Hz, 1H, —CH2—CH—N—), 4.30(dd, J=6.3 and 14.7 Hz, 1H, —NH—CH2—), 4.23(dd, J=5.9 and 14.6 Hz, # 1H, —NH—CH2—), 3.36-3.22 (m, piperidinyl and —N—CH2CH3), 2.67(dd, J=9.9 and 14.4Hz, 1H, —CO—CH2), 2.24(dd, J=5.1 and 14.1Hz, 1H, —CO—CH2—), 1.45(br, 6H, piperidinyl), 1.10(t, J=6.9Hz, 3H —N—CH2CH3); 13C NMR(75MHz, CDCl3)δ # 169.3, 166.5, 163.1, 155.1, 136.2, 135.4, 134.8, 133.6, 129.9, 128.8, 126.5, 125.9, 124.4, 121.1, 118.9, 116.1, 55.3, 48.2, 42.6, 41.4, 25.1. 23.5, 14.0.

Test for Biological Activity

In order to screen an effective T-type calcium channel blocker, the compounds prepared in the above Examples were subjected to a test for channel inhibitory effect using frog unfertilized oocytes expressing α1H of T-type calcium channel as a primary screening method. As a result of the primary screening, the candidate compounds for blocking T-type calcium channel blockers showing 50% or more inhibitory effect were selected and subjected to the test for T-type calcium channel activity according to an electrophysiological whole cell patch clamp method. Such method uses mammalian HEK 293 cell line selectively expressing α1G among T-type calcium channel encoding genes, wherein the α1G is mainly expressed at nerve cells (derived from human kidney cancer cells and it was established by Prof. Edwards Ferez-Reyes of University of Virginia in Virginia, U.S.A.). The candidate compounds confirmed their T-type calcium channel blocking activities were subjected to cytotoxicity test according to 3-(4,5-dimethylthiazole-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay. As a result, it has been found that the compounds of the present invention show good inhibitory effect on the T-type calcium channel.

TEST EXAMPLE 1-1

Preparation of Unfertilized Xenopus oocytes and cRNA Synthesis of α1H T-Type Calcium Channel

In order to express a gene encoding T-type calcium channel α1H (Cav3.2) (Cribbs, L. L. et al., Circ. Res., 1998, 83, 103-109) in unfertilized Xenopus oocytes, pGEM-HEA was treated with restriction enzyme AflII to obtain a DNA fragment containing 5′-terminal region having the T-type calcium channel cDNA (AF051946). cRNA having a corresponding sequence to that of the fragment was synthesized using T7 RNA polymerase according to the manufacturer's instructions (mMESSAGE mMACHINE kit, Ambion, Austin, U.S.A.). The synthesized cRNA was quantified by measuring the O.D. value with a spectrophotometer. At this time, unfertilized oocytes were prepared from female Xenopus laevis (Xenopus I, U.S.A.) according to the following method. After the frog's abdomen was incised by about 1 cm, three to four lobes were detached therefrom with scissors and separated into small pieces to which several oocytes were attached. The small pieces were hydrolyzed in OR solution (82.5 mM NaCl, 2.5 mM KCl, 1 mM MgCl2, 5 mM HEPES, pH 7.6) and supplemented with collagenase type IA (Sigma, U.S.A.) to remove defolliculation. After selecting healthy oocytes with a dissecting microscope, they were soaked in SOS solution (100 mM NaCl, 2 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 5 mM HEPES, 2.5 mM pyruvate, 50 μM/ml gentamicin, pH 7.6) for 3 to 4 hours to revitalize them. 2 to 5 ng of cRNA was injected into each oocyte using Nano-injector. The oocytes were subjected to a test in order to examine the electrical properties of the channel expressed therefrom 4 to 5 days after the injection while being maintained at 18° C.

TEST EXAMPLE 1-2

Examination of Electrophysiological Property of α1H T-Type Calcium Channel using a Two-Electrode Voltage Clamping Method

The current of the calcium channel expressed from the Xenopus unfertilized oocytes was measured according to a two-electrode voltage clamping method. The current was measured in 10 mM Ba2+ solution (10 mM Ba(OH)2, 90 mM NaOH, 1 mM KCl, 0.1 mM EDTA, 5 mM HEPES, pH was adjusted to 7.4 with methanesulfonic acid). At this time, the voltage clamp and current measurement were regulated with an amplifier for unfertilized oocytes (Model OC-725C, Warner Instrument Corp., U.S.A.), and analog signals were converted into digital signals using Digidata 2000A (Analog-Digital converter, Axon Instrument). The acquisition, storage and analysis of all data were recorded in Pentium IV computer via pCLAMP8. The data were mainly collected at 5 KHz and filtered at 1 KHz (Model 902 filter; Frequency devices located at Harverhill, Mass., U.S.A.). The T-type current was generated by imposing test electric potential of −20 mV every 15 seconds on the unfertilized oocytes, the potential of which was fixed at −90 mV. . A blocking percentage was calculated by comparing the potentials before and after the drug treatment. The results are shown in Table 2.

TEST EXAMPLE 2 Methods for Culturing HEK 293 Cells and Measuring T-Type Calcium Channel Activity using an Electrophysiological Method

HEK 293 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (v/v) in 36.5° C. humidified incubator (95% air-5% CO2). The culture solution was replaced with a fresh medium every 3 to 4 days and the cultured cells were subjected to sub-culture every week. At this time, the culture solution was treated with G-418 (0.5 mg/ml) solution so that only HEK 293 cells expressing α1G T-type calcium channel can grow. The cells used for the T-type calcium channel activity assay were cultured on a cover slip coated with poly-L-lysine (0.5 mg/ml) whenever sub-cultured and their calcium channel activity was recorded 2 to 7 days after the cultivation. The current of the T-type calcium channel at a single cell level was measured according to an electrophysiological whole cell patch clamping method using EPC-9 amplifier (HEKA, German). At this time, a cell exterior solution [140 mM NaCl, 2 mM CaCl2, 10 mM HEPES (pH 7.4)] and a cell interior solution [KCl 130 mM, HEPES 10 mM, EGTA 11 mM, MgATP 5 mM (pH 7.4)] were employed. The inward current caused by the T-type calcium channel activation was measured according to a T-type calcium channel protocol activated at low current. Such current occurs when the cells were converted into a whole-cell recording mode by stabbing a microglass electrode having 3-4 MΩ resistance, which was filled with the cell interior solution into a single cell and depolarized at −30 mV (50 ms duration period) every 10 seconds with fixing membrane potential to −100 mV.

TEST EXAMPLE 3 Method for Screening T-Type Calcium Channel Blockers using an Electrophysiological Method

In order to confirm whether the cells and methods used in Test Example 2 are a suitable screening system for selecting T-type calcium channel blockers, the results obtained in Example 2 were compared with those of α1G T-type calcium channel study reported in a public document (Monteil, A. et al., J. Biol. Chem. 275, 6090-6100, 2000). As can be seen in FIG. 1, it has been confirmed that since the screening system of the present invention showed 1) the maximum activation at low voltage of −30 mV (FIG. 1), 2) the fast activation-inactivation of the activated current (FIG. 2), and 3) the same IC50 as those of Ni2+ and Mibefradil known as T-type calcium channel blockers (FIGS. 3 and 4), it is suitable for screening T-type calcium channel blockers. Thus, the candidate compounds were subjected to a test for their inhibitory effects on the T-type calcium channel according to the screening system of the present invention, as follows. Each compound was dissolved in 100% dimethylsulfoxide (DMSO) to prepare 10 mM stock solution. The inhibitory effect on the T-type calcium channel current was examined in 10 μM sample solution (containing 0.1% DMSO) prepared by diluting the stock solution by 1000-fold. The cells were treated with each compound at a concentration of 10 μM for 30 to 60 sec with the cell exterior solution. Then, the inhibition level of peak current caused by the compound was calculated as a percentage and shown in FIG. 5.

TEST EXAMPLE 4 Analysis for Cytotoxicities of T-Type Calcium Channel Blockers using MTT Assay

In order to analyze cytotoxicities of the T-type calcium channel blockers in HEK 293 cells, MTT assay was conducted as follows. The cultured HEK 293 cells were treated with each compound at concentrations of 10 μM and 100 μM. At this time, the cells treated with a solvent (i.e., 0.1% DMSO) were used as a negative control and the cells treated with H2O2 (125 μM) inducing cytotoxicity were used as a positive control. After 6 hours of drug treatment, the cells were treated with 50 μl of MTT (1 mg/ml) dissolved in PBS for 4 hours. Then, the reaction mixture was centrifuged to remove a supernatant and formazan crystals thus obtained were dissolved in 100 μl of DMSO. The solution's absorbance was measured at 560 nm with an automated spectrophotometric plate reader. As a result, all the compounds showing 50% or more inhibitory effect on HEK 293 cells did not show any cytotoxicity at a concentration of 10 μM and some of them showed cytotoxicity only at a high concentration (100 μM) (FIG. 6).

The results of examining the inhibitory effects of the compounds of the present invention on the T-type calcium channel in Xenopus unfertilized oocytes (α1H) and HEK 293 cells (α1G) are summarized in Table 2.

TABLE 2 Xenopus HEK293 oocyte cells (a 1G) Compound (a 1H) at 10 μM (KIST-Code) Formula at 100 μM (IC50, μM) 05001 77.0 90.1 (0.9) 05026 63.8 40.5 (21.6) 05027 20.9 NT 05028 70.3 29.0 (35.8) 05029 32.7 NT 05031 14.8 NT 05032 14.2 NT 05033 38.9 NT 05034 91.9 92.3 (2.5) 05040 66.8 43.5 (14.4) 05041 84.7 89.9 (0.25) 05042 80.5 89.9 (0.20) mibefradil 86.0 95.9 (0.84)

As can be seen in Table 3, KYS05001, KYS05041 and KYS05042 showed higher selectivity for the calcium channel than the sodium channel. Further, in case of examining the selectivity for the sub-types of the calcium channel, KYS05041 and KYS05042 showed relatively lower selectivity. This is because it inhibited both the T-type (LVA) and N-type (HVA) calcium channels. However, KYS05001 showed higher selectivity and selectively inhibited only the T-type (LVA) calcium channel.

Claims

1. A 3,4-dihydroquinazoline derivative of Formula 1 or a salt thereof:

wherein, n is an integer ranging from 1 to 4;
R1 is selected from the group consisting of hydrogen, hydroxy, halogen, nitro, C1-C8 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted aryl and heteroaryl, C1-C6 alkoxy, C3-C6 cycloalkoxy, (aryl or heteroaryl)oxy, C1-C6 thioalkoxy, C3-C6 cyclothioalkoxy, (aryl or heteroaryl)thiooxy and amino;
R2 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkoxyalkyl, C1-C6 alkenyl; substituted or unsubstituted aryl and heteroaryl; 4-morpholinyl; piperazinyl having a random substituent at the 4th position; 1-pyrrolidinyl; 1-piperidinyl; or —NR1R2, wherein R1 and R2 are each independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl and heteroaryl;
R3 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkoxyalkyl, substituted or unsubstituted aryl and heteroaryl;
R4 is X—(CH2)n—Y—S(O)m—NH-Z, wherein X is oxygen or nitrogen; n is an integer ranging from 1 to 4; Y is substituted or unsubstituted C3-C6 cycloalkyl, aryl or heteroaryl; m is an integer ranging from 0 to 2; Z is selected from the group consisting of substituted or unsubstituted C3-C6 cycloalkyl, aryl and heteroaryl.

2. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-(N-benzylacetamido)-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline.

3. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-(N-benzylacetamido)-3-phenyl-2-(morpholin-1-yl)-3,4-dihydroquinazoline.

4. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-(N-benzylacetamido)-3-phenyl-2-(4-methylpiperazinyl)-3,4-dihydroquinazoline.

5. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-[N-(4-nitrobenzyl)acetamido]-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline.

6. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-{N-[4-(4-methylbenzenesulfonylamido)benzyl]acetamido}-3-phenyl-2-(piperidine-1-yl)-3,4-dihydroquinazoline.

7. The 3,4-dihydroquinazoline derivative of claim 1 or the salt thereof, which is 4-{N-[4-(4-fluorobenzenesulfonylamido)benzyl]acetamido}-3-phenyl-2-(piperidin-1-yl)-3,4-dihydroquinazoline.

Patent History
Publication number: 20050197351
Type: Application
Filed: Dec 20, 2004
Publication Date: Sep 8, 2005
Patent Grant number: 7271260
Inventors: Yong Sup Lee (Seoul), Jae Lee (Seoul), Hyewhon Rhim (Seoul)
Application Number: 11/018,786
Classifications
Current U.S. Class: 514/266.100; 514/266.200; 514/266.220; 544/283.000; 544/284.000